Pharmacodynamics of GSK961081, a bi-functional molecule, in patients with COPD

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Abstract

GSK961081 is an inhaled bi-functional molecule with both muscarinic antagonism and β2-agonism (MABA) properties.

This randomised, double-blind, double-dummy, crossover study evaluated 14 days treatment with the MABA GSK961081 400 μg and 1200 μg once daily and tiotropium 18 μg once daily plus salmeterol 50 μg twice daily (TIO + SAL), versus placebo in 50 patients with moderate COPD. The primary endpoint was forced expiratory volume in 1 s (FEV1) at 24 h on Days 1 and 14.

MABA 400 (n = 29), MABA 1200 (n = 32) and TIO + SAL (n = 41) resulted in significant increases in FEV1 over 24 h. Mean (95% CI) 24 h trough FEV1 (L) values relative to placebo (n = 43) were, for Day 1, MABA 400: 0.141 (0.060, 0.222); MABA 1200: 0.184 (0.105, 0.263); TIO + SAL: 0.162 (0.092, 0.231); for Day 14, MABA 400: 0.115 (0.024, 0.205); MABA 1200: 0.168 (0.080, 0.255); TIO + SAL: 0.103 (0.026, 0.180). Onset of bronchodilation was faster for both MABA doses versus TIO + SAL. No clinically relevant systemic pharmacodynamic effects were observed. Adverse events were similar across groups; however tremor (n = 2, MABA 1200), dysgeusia (n = 2, MABA 1200; n = 2, MABA 400) and dry mouth (n = 1, MABA 1200) were reported after GSK961081 only.

GSK961081 demonstrated sustained bronchodilation similar to TIO + SAL, but with a more rapid onset, and was well tolerated at the tested doses.

Introduction

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disease and a major cause of chronic morbidity and mortality worldwide. The main goals of COPD management are to relieve symptoms, improve activity/exercise tolerance, prevent and treat exacerbations, reduce mortality risk and improve health status [1], [2]. Bronchodilators are central to the symptomatic management of COPD, and inhaled β2-agonists and inhaled muscarinic antagonists are the most frequently used bronchodilators, including both short-acting and long-acting agents [1]. All categories of bronchodilators have been shown to improve lung function parameters [3], [4], [5], [6] and increase exercise capacity in COPD [7], [8], [9]. Long-acting bronchodilators have also been shown to reduce the frequency of exacerbations [10], [11], [12] and to improve health status [10], [12], [13].

For COPD patients who remain uncontrolled on maintenance monotherapy, combining different classes of bronchodilators may provide greater bronchodilation [1], [2]. Long acting β-agonists (LABAs) activate β2 receptors resulting in smooth muscle relaxation (sympathomimetic) and long acting muscarinic antagonists (LAMAs) inhibit the bronchoconstriction which is mediated via muscarinic receptors (anticholinergic) [14], [15]. Targeting bronchodilation via two distinct mechanisms may be expected to address the variation in response to treatment within and between patients and several studies have demonstrated a superior bronchodilation effect of combining a LABA with a LAMA compared with individual agents alone [16], [17], [18], [19], [20].

Bi-functional (or dual pharmacophore) muscarinic β2-agonist molecules (MABA) represent a new approach to combined bronchodilator therapy by combining muscarinic antagonism (MA) and β2-agonism (BA) in a single molecule. A benefit of this approach is that it circumvents the potential problem of formulating different drugs in one inhaler, providing a fixed ratio of MA and BA with simplified formulation and pharmacokinetics compared with combination therapy [14]. Another key advantage of bi-functional molecules is the potential to provide a simpler route to a triple action therapy (for example dual combination with an inhaled corticosteroid [ICS]) versus combining three different molecules in a single inhaler).

GSK961081 is an inhaled bi-functional molecule currently in clinical development. The results of in vitro binding and functional studies showed GSK961081 to be a potent functional antagonist of muscarinic receptors as well as a potent, selective and full agonist at the β2-adrenoceptor in cellular systems [21]. Tissue bath experiments using isolated tracheal rings from the guinea pig which had been precontracted with histamine (±10 μM propranolol) to assess BA activity or with methacholine (±10 μM propranolol) to assess MABA and BA activity respectively, demonstrated that the combined action of both mechanisms was greater than either one alone. In a pre-clinical in-vivo study, in which guinea pigs were dosed by whole body inhalation with GSK961081 or sterile deionised water and challenged with incremental doses of methacholine or histamine, GSK961081 produced significant and sustained bronchoprotection via the MA, BA and MABA mechanisms, and the bronchoprotection achieved with the MABA was significantly greater than that with either the MA or BA alone [22]. The selectivity of GSK961081 at cloned muscarinic acetylcholine receptor subtypes shows the compound to have equal affinity for the M3 and M2 receptors, and approximately 7-fold more affinity for M3/M2 than for the M1 receptor [21]. In preclinical studies a metabolite with less beta-agonist potency and a metabolite with less anticholinergic potency than the parent compound have been identified. These metabolites have been assayed for in man although not detected.

The aims of the current study were to determine the safety, tolerability, pharmacokinetics and pharmacodynamics, both pulmonary and systemic, of inhaled GSK961081 in patients with COPD.

Section snippets

Patients

Males and females (non-child bearing) aged 40–75 years with moderate COPD according to ATS/ERS guidelines [2], including a post-bronchodilator forced expiratory volume in 1 s (FEV1) between 50 and 80% of predicted normal and a post-bronchodilator FEV1/forced vital capacity (FVC) ratio ≤ 0.7 were included. All patients were either smokers or former smokers and had a minimum 10 year pack smoking history and demonstrated reversibility to both salbutamol and ipratropium bromide, defined as an

Patients

Fifty patients with COPD were randomly assigned to receive 3 out of 4 study treatments in a cross-over design (Fig. 1). Three patients were withdrawn during the study, one due to an exacerbation of COPD requiring oral corticosteroid treatment, the other two due to withdrawal of patient consent. The difference in patient numbers between treatment groups (i.e. fewer number of patients randomised to the MABA treatments) was due to the treatment sequencing requirement that patients randomised to

Discussion

This was the first study to evaluate the bronchodilatory effects of a new bi-functional molecule, the MABA GSK961081, in patients with moderate COPD. Fourteen days of treatment with either MABA dose resulted in sustained bronchodilation that was statistically significant at 24 h post-dose compared with placebo and comparable to that seen with TIO + SAL. After 14 days' treatment, a greater than 150 mL improvement was observed at 12 h for all active treatments, and for the MABA 1200 dose at 24 h.

Disclosure statement

Within the last five years, EDB has received honoraria for lectures and/or advisory board membership from Actelion, AlkAbello, Almirall, Amgen, Astra Zeneca, Boehringer Ingelheim, Chiesi, Forest, Hoffmann la Roche, GlaxoSmithKline, Merck, Napp Pharma, Novartis, Nycomed/Takeda and Pfizer, and his institution has received funding for clinical trials from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Hoffmann la Roche, GlaxoSmithKline, Merck, Morria Biopharmaceuticals, Novartis, Nycomed,

Acknowledgements

Funding for this study was provided by GlaxoSmithKline (Study number: MAB104958, NCT00478738). The authors acknowledge the statistical support of Chang-Qing Zhu and Nigel Dallow and the clinical support of Maurice Leonard. The authors acknowledge the investigators, their staff and patients at the 5 clinical trial sites: Parexel International GmbH, Berlin, Germany; Mainz University hospital, Department of Pulmonary Medicine, Germany; University of Cape Town Lung Institute, South Africa;

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